Oncothermia Journal 6:11-25 (2012)

Clinical study for advanced pancreas cancer treated by

oncothermia

Dani A, Varkonyi A, Magyar T, Kalden M, Szasz* A.

() Oncology Department, Vaszary K. Hospital, Petofi S. u. 18, Esztergom, Hungary

() Polyclinic XIV, Jokai u. 3. Budapest, Hungary

() Oncology Department, Peterfy Hospital, Peterfy S. u. 1, Budapest, Hungary

() VeraMed Klinik, Meshede, Germany

() Department Biotechnics, St. Istvan University, Godollo, Hungary

Dr. A. Szasz; Szent Istvan krt.20. Budapest, 1137, Hungary, Email: Szasz.Andras@gek.szie.hu

10 Oncothermia Journal, September 2012

Clinical study for advanced pancreas cancer treated by oncothermia

Abstract
Pancreas cancer (PCA) is an aggressive, common malignant tumor. We present two retrospective
clinical studies of PCA done in two medical centers (HTT-MED Day-clinic and Peterfy
Hospital). Both of the centers made the treatments by oncothermia in combination with the
conventional tumor-therapies. We present the data from both centers and make a metaanalysis of
the data as well. Results show a remarkable survival benefit for the patients compared to the
historical data. The comparison of the studies shows a good correspondence in the data, which
strengthens the reliability of the studies, and points out the feasibility of the oncothermia
application on PCA.
Keywords: pancreas cancer, clinical-study, hyperthermia, oncothermia, survival-time, comparison.

Introduction, objective
Pancreas cancer [PCA, (topographic ICD: C25)] is a very aggressive tumor, one of the major
unsolved
health
problems
of
the
present,
[
1].The PCA is one of the most aggressive malignant disease with rapid progression-rate and
short survival-time. Despite the massive efforts to find the adequate therapy, relatively low
progress could be achieved in survival-rate of the disease.
The prognosis of the disease is extremely poor; only less than a quarter of the patients are
operable, and less than a quarter of those survive to 5 years, and its incidence does not decrease
in the past five years, [2]. Its gold-standard management is the resection, but most of the patients
are unresectable, [3]. The radiation therapy is more palliative than curative, [4], [5]. This is the
reason, why the chemotherapy in this disease has an especially important role. The subsequent
reviews point out the importance of the adjuvant and neoadjuvat therapies, [6], [7], [8], and the
Gemcitabine (Gemzar) + 5-flourouracil + leucovorin combination had shown a remarkable
efficacy [9], [10], [11], [12], see Table 1.
Pts.#
16
16
36
163
164
12
16
54
34
26
24
52
44
48
28
24
24
12
41
26
27
42
29
25
62
64
13
11
19
24
23

RR (%)
25
25
14

1 y surv. (%)

5.25
4.4
5.4
6.7

25
31
3.7
17
19.3
8
31
13
9
29
38
8.3
11
19.2
7.4
5.7
10
8
25.9
29
23
9.1
0
35
34.7

Median surv. (m)

9.6
7
5.7
8.5
6
6
8
2.5

22
28

6
8.5
8.2
10.3
7
6.5
4
9.6
9

9
9

Ref.
[13]
[14]
[15]
[16]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36], [37]
[38], [39]
[40]
[41]
[42]
[43]

Oncothermia Journal, September 2012

11

38
24
14
42
40
25
49
43
14
21
16
15
12

5
13
7
26
20
20
58
19
14
19
19
13
25

9.3
7.5
6.1
7.1
6.75
11
9
5.5
4.7
8

[44], [45], [46]

[47]
[48]
[49], [50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]

Table 1. Clinical studies on effeicacy of Gemzar combination

Hyperthermia (HT), combined with radiotherapy (RT) and chemotherapy (CT), seems to be a
promising method for cancer treatment, although many of the underlying molecular mechanisms
of this combination treatment are not properly understood yet. Although some widely accepted
effects had been recognized:
It has been shown that an increase in temperature can cause vasoconstriction in certain tumors
leading to decreased blood perfusion and heat conduction, and also inhibit angiogenesis [60],
[61], [62]. At the same time, the elevated temperature causes vasodilation in the healthy tissues,
leading to its increased blood perfusion and heat conduction [63]. These effects functioning like
an effective heat trap [64], selectively increase the temperature in the tumor [65]. Furthermore it
has long been known that hyperthermia can cause softening or melting of the lipid bilayer [66],
[67], [68], it can change lipid-protein interactions [69], and it can denature proteins [70]. All of
these events can significantly disrupt a tumor cells capacity to divide. It is shown, that the
increased temperatures cause a drastic change in transmembrane currents [71] and structurally
alters the transmembrane proteins causing a change in active membrane transport and membrane
capacity [72], leading to substantial changes in potassium, calcium, and sodium ion gradients
[73], membrane potential [74], cellular function [75], [76], and induce thermal blocks of
electrically excitable cells [74], [77]. Hyperthermia changes the pH values by increasing the
biochemical reaction rates [78] and therefore also the metabolic rate. The lack of the oxygen for
this forced metabolism results hypoxia [79] and the anaerobe metabolism produces lactate [80]
and cell destruction by acidosis. Furthermore, the increased metabolism can significantly
decrease the cellular ATP stores leading to increased cell destruction [80]. The DNA replication
process is also altered by heat. The increased temperatures can slow down or even block DNA
replication [81], [82], as well as stimulate the immune system [81], with observed increases in
natural killer cell activity [83]. Moreover, the elevated temperature distributes tumor-specific
antigens on the surface of various tumor cells [84] and assists in their secretion into the
extracellular fluid [85]. It is important to mention for the clinical outcome the improvement in
the quality of life due to the significant pain reduction [86], which can be prolonged and
enhanced by the electric field using TENS effects [87]. This pain-reduction has special
importance at such painful disease like PCA. Additionally, hyperthermia is an ideal combination
therapy. It has low toxicity, mild side effects, and has been shown to provide synergies with
many of the traditional treatment modalities. It enhances the effect of chemotherapy [88], [89];
and also has pronounced advantages for surgical interventions.
One of the most advanced treatment HT-modalities devoted to oncology is oncothermia (OT),
[90], [91]. Due to the limited effectiveness of established therapies, OT could be one of the
important future methods to improve the treatment facilities of PCA, [92], [93].
Our objective in this article is to present a retrospective clinical study for PCA. The study
concentrates on the effects of the survival time as one of the most important factors to measure
the success of a treatment in oncology.

12 Oncothermia Journal, September 2012

The retrospective data are indications only, the prospective, randomized, controlled study should
clarify the situation as according to evidence based medicine. However, we present data from two
study-places, showing their similar results, and also present a comparison of the first year survival
by oncothermia with two more independent clinics.

Method
The present results are obtained from an open-label, single-arm, retrospective study. The
involved patients are being analyzed according to an intention-to-treat (ITT) schedule.
Recruiting time was from Apr. 1997 to Aug. 2002, all together 64 months. The primary check of
the efficacy of a curative method in such a lethal kind of disease is the survival time. The
primary endpoints of the present study therefore were the overall survival oncothermia treatment
time (OS) and the survival time from the first oncothermia treatment (oncothermia treatment
survival time, OSO). The date of death (or alive) were checked by the Hungarian National Death
Register, so the actual and accurate data were collected. The latest check of the deaths was 31.
December of 2003.
The evaluation methods were: descriptive biostatistics, log-rank survival tests (Kaplan-Meier
plot), and comparison with large studies and databases and/or local historical data. In order to
support the reliability of the retrospective data-set, two independent hospitals were involved in
the present study. One is the Peterfy Hospital, Budapest (PFY). It is a governmental hospital
involved in the regular health-service network. The other one is a private day-clinic (HTT-Med
Polyclinics, (HTT)), serving the patients only on private basis. The two trial-places were in tight
information-contact, making the treatments with the same practical conditions and guidelines.
Patients were dominantly in late/advanced stages, where the traditional oncotherapies were
unsuccessful.
Inclusion criteria were: (1) Inoperable or sub-totally resected or recurrent primary pancreas

tumor, (2) progression after surgery and/or chemo-therapy, (3) Karnofsky Performance Score

(KPS) > 40%. and the inclusion was irrespective of the localization of the lesion in the pancreas.

Most of the patients failed to respond to any of the applied conventional therapies.

Exclusion criteria were only the well-known contraindications of the oncothermia method

(metallic implants or replacements in the treated area, missing heat-sense in the treated area,

pacemaker or other field-sensitive implants in the patient).

The study had a couple of possible negative biases: (1) the treatment is paid or co-paid by the
patients, who do it on a voluntary basis (ITT) in strict control of the oncologist who was
responsible for the patient treatment till that time; (2) no randomized control arm exists, the trial
is compared to the historical control or to the available literature.
However, the present study had a few possible positive biases as well: (1) patients were treated
in their advanced stages, when other treatments had failed and/or were not possible; (2) the
involved clinics are not equipped so well as the special institutes/universities; (3) the involved
patients had no extra trial-attention.
The safety of the method is proven. It has been applied over 15 years in clinical practices. No
serious safety problem has been reported about the oncothermia treatments. The devices are
approved according to the European Medical Device Directive (CE/MDD) and those are under
permanent vigilance system. The treatment dose is personalized, fitted for the actual status of the
given patient.
Oncothermia Journal, September 2012

13

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